Mutation of p53, inherited in some individuals with Li-Fraumeni syndrome (LFS), is a critical event in the[unreadable] elaboration of many tumors of diverse origin. Most mutations of p53 are single nucleotide changes that alter[unreadable] critical amino acids in the DNA-binding domain rather than alterations that delete the p53 gene. The[unreadable] prevalence of p53 missense mutations coupled with in vitro data has led to the hypothesis that mutant p53[unreadable] has additional properties that make it more detrimental for proper cell cycle regulation and more[unreadable] advantageous to the dividing cell. To test this hypothesis in vivo and model human LFS more accurately, we[unreadable] have generated mouse models inheriting the p53R172H mutation (corresponding to the p53R175H hotspot[unreadable] in human cancers). This mutation disrupts the conformation of p53 resulting in a protein that is tumorigenic in[unreadable] cooperation with ras, and readily immortalizes cells. Mice with the p53R172H mutation have gained[unreadable] additional tumorigenic properties and also exhibit a dominant-negative phenotype. Metastasis is rampant in[unreadable] p53R172H/+ mice as opposed to mice lacking one p53 allele. Additional experiments are needed to[unreadable] ascertain the events leading to tumorigenesis, metastasis, stability of the mutant p53, and the dominantnegative[unreadable] nature of the mutation. To examine the ability of p53R172H to cooperate with Brcal deletion,[unreadable] another common alteration that leads to breast cancer, crosses with Brca1+/- mice in a background[unreadable] sensitive to beast cancer will be performed. An important question that will be addressed in these studies is[unreadable] what other molecular changes, examined by CGH and Affymetric arrays, cooperate with mutant p53 in the[unreadable] genesis of different kinds of cancers. Lastly, since the type of p53 missense mutation may also contribute to[unreadable] different phenotypes, another p53 missense mutation will be generated in mice. The p53R245W mutation[unreadable] represents a DMA contact mutant that alters an arginine amino acid involved in direct contact to DNA.[unreadable] p53R245W is also transcriptionally inactive, but cannot immortalize cells. The p53R245W mutation in[unreadable] another hot spot mutation inherited in LFS patients. Comparison of the two classes of p53 mutants[unreadable] (conformation versus contact) should yield insights into the role of these mutants in tumorigenesis. Our[unreadable] studies suggest that treatment of a patient will have to be tailored not only to the kind of tumor that develops,[unreadable] but to the specific p53 missense mutation identified in the tumor as well.[unreadable] The research outlined in this application is directly relevant to public health in that it proposes to study a[unreadable] gene, p53, that is often altered in different kinds of cancers. The study aims to understand the nature of p53[unreadable] mutations and of other changes that cooperate with this defect. These studies may identify novel therapeutic[unreadable] targets.[unreadable]